Christopher Steward

Diffusion Tensor Imaging in Glioblastoma Multiforme and Brain Metastases: The Role of p, q, L, and Fractional Anisotropy

BACKGROUND AND PURPOSE: Microinvasive tumor cells, which are not detected on conventional imaging, contribute to poor prognoses for patients diagnosed with glioblastoma multiforme (GBM, WHO grade IV). Diffusion tensor imaging (DTI) shows promise in being able to detect this infiltration. This study aims to detect a difference in diffusion properties between GBM (infiltrative) and brain metastases (noninfiltrative). MATERIALS AND METHODS: For 49 tumors (30 GBM, 19 metastases), DTI measures (p, q, L, and fractional anisotropy [FA]) were calculated for regions of gross tumor (excluding hemorrhagic and necrotic core), peritumoral edema, peritumoral margin (edema most adjacent to tumor), adjacent normal-appearing white matter (NAWM), and contralateral white matter. Parametric and nonparametric statistical tests were used to determine significance, and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: Mean values of p, L, and FA from regions of signal-intensity abnormality differed from those of normal brain in both tumors. The mean q value did not differ significantly compared with that in normal brain in any region in metastases or in adjacent NAWM of GBM. For GBM compared with metastases, q and FA were significantly lower in gross tumor (P < .001) and q was significantly lower in peritumoral margin (P < .001), which may be due to tumor infiltration. Significant overlap was present, which was reflected in the ROC curve analyses (area under the curve values from 0.732 to 0.804). CONCLUSIONS: DTI may be used to help differentiate between GBM and brain metastases. The results also suggest that DTI has the potential to assist in detecting infiltrative tumor cells in surrounding brain.

White and gray matter alterations in adults with Niemann-Pick disease type C A cross-sectional study

Objective: Niemann-Pick disease type C (NPC) is a progressive neurovisceral disorder with disrupted intracellular cholesterol metabolism that results in significant alterations to neuronal and axonal structure. Adult patients present with ataxia, gaze palsy, impaired cognition, and neuropsychiatric illness, but the neural substrate has not been well-characterized in vivo. Our aim was to investigate a well-characterized sample of adults with confirmed NPC for gray and white matter abnormalities. Methods: We utilized a combination of optimized voxel-based morphometry of T1-weighted images and tract-based spatial statistics of diffusion tensor images to examine gray matter volume and white matter structural differences in 6 adult patients with NPC and 18 gender- and age-matched controls. Results: Patients with NPC demonstrated bilateral gray matter reductions in large clusters in bilateral hippocampus, thalamus, superior cerebellum, and insula, in addition to smaller regions of inferoposterior cortex. Patients demonstrated widespread reductions in fractional anisotropy in major white matter tracts. Subsequent analysis of measures of axial and radial diffusivity suggest that these changes are contributed to by both impaired myelination and altered axonal structure. Conclusions: Findings in gray matter areas are broadly consistent with human and animal studies of selective vulnerability of neuronal populations to the neuropathology of NPC, whereas more widespread white matter changes are consistent with the hypothesis that disrupted myelination and axonal structure predate changes to the neuronal cell body. These findings suggest that volumetric analysis of gray matter and diffusion tensor imaging may be useful modalities for indexing illness stage and monitoring response to emerging treatment.

Incidence of cerebral microbleeds in preclinical Alzheimer disease

Objective: We sought to determine the incidence and associations of lobar microbleeds (LMBs) in a longitudinal cohort with 11C–Pittsburgh compound B (PiB) PET imaging. Methods: One hundred seventy-four participants from the observational Australian Imaging, Biomarkers and Lifestyle Study of Ageing (97 with normal cognition [NC], 37 with mild cognitive impairment [MCI], and 40 with Alzheimer disease [AD] dementia) were assessed at 3 time points over 3 years with 3-tesla susceptibility-weighted MRI and 11C-PiB PET. MRIs were inspected for microbleeds, siderosis, infarction, and white matter hyperintensity severity, blind to clinical and PiB findings. Neocortical PiB standardized uptake value ratio, normalized to cerebellar cortex, was dichotomized as positive or negative (PiB+/−, standardized uptake value ratio >1.5). Annualized LMB incidence was calculated, and logistic regression was used to determine the association of incident LMBs with PiB, APOE ε4+ status, and cerebrovascular disease. Results: LMBs were present in 18.6% of NC, 24.3% of MCI, and 40% of AD participants (p < 0.05 vs NC). LMB incidence was 0.2 ± 0.6 per year in NC participants, 0.2 ± 0.5 in MCI, and 0.7 ± 1.4 in AD (p < 0.03 vs NC) and was 6-fold higher in PiB+ than PiB-NC. Incident LMBs were associated with age, APOE ε4+, PiB+, and baseline LMBs. Incidence of multiple LMBs was also associated with lacunar infarction and white matter hyperintensity severity. Conclusions: Older age, baseline LMBs, higher β-amyloid burden, and concomitant cerebrovascular disease may all confer higher risk of incident LMBs. This should be considered when designing protocols for amyloid-modifying clinical trials.

Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity

High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.

Contralesional thalamic surface atrophy and functional disconnection 3 months after ischemic stroke.

Background: Remote structural and functional changes have been previously described after stroke and may have an impact on clinical outcome. We aimed to use multimodal MRI to investigate contralesional subcortical structural and functional changes 3 months after anterior circulation ischemic stroke. Methods: Fifteen patients with acute ischemic stroke had multimodal MRI imaging (including high resolution structural T1-MPRAGE and resting state fMRI) within 1 week of onset and at 1 and 3 months. Seven healthy controls of similar age group were also imaged at a single time point. Contralesional subcortical structural volume was assessed using an automated segmentation algorithm in FMRIBs Integrated Registration and Segmentation Tool (FIRST). Functional connectivity changes were assessed using the intrinsic connectivity contrast (ICC), which was calculated using the functional connectivity toolbox for correlated and anticorrelated networks (Conn). Results: Contralesional thalamic volume in the stroke patients was significantly reduced at 3 months compared to baseline (median change -2.1%, interquartile range [IQR] -3.4-0.4, p = 0.047), with the predominant areas demonstrating atrophy geometrically appearing to be the superior and inferior surface. The difference in volume between the contralesional thalamus at baseline (mean 6.41 ml, standard deviation [SD] 0.6 ml) and the mean volume of the 2 thalami in controls (mean 7.22 ml, SD 1.1 ml) was not statistically significant. The degree of longitudinal thalamic atrophy in patients was correlated with baseline stroke severity with more severe strokes being associated with a greater degree of atrophy (Spearmans rho -0.54, p = 0.037). There was no significant difference between baseline contralesional thalamic ICC in patients and control thalamic ICC. However, in patients, there was a significant linear reduction in the mean ICC of the contralesional thalamus over the imaging time points (p = 0.041), indicating reduced connectivity to the remainder of the brain. Conclusions: These findings highlight the importance of remote brain areas, such as the contralesional thalamus, in stroke recovery. Similar methods have the potential to be used in the prediction of stroke outcome or as imaging biomarkers of stroke recovery.

A Phase IIa Randomized Control Trial of VEL015 (Sodium Selenate) in Mild- Moderate Alzheimer's Disease

BACKGROUND There is increasing interest in targeting hyperphosphorylated tau (h-tau) as a disease modifying approach for Alzheimers disease (AD). Sodium selenate directly stimulates the activity of PP2A, the main enzyme responsible for h-tau dephosphorylation in the brain. OBJECTIVE This study assessed the safety and tolerability of 24-week treatment with VEL015 (sodium selenate) in AD. Investigating the effects of VEL015 on cognitive, CSF, and neuroimaging biomarkers of AD were secondary, exploratory objectives. Data were used to identify biomarkers showing most promise for use in subsequent efficacy trials. METHODS A 24-week, multicenter, Phase IIa, double-blinded randomized controlled trial. Forty patients aged ≥55 y with mild-moderate AD (MMSE 14-26) were randomized to supranutritional (VEL015 10 mg tds [n = 20]) and control (VEL015 320μg tds [n = 10] or placebo [n = 10]) groups. Patients were regularly monitored for safety, adverse events (AEs), and protocol compliance. Exploratory biomarkers included cognitive tests, neuroimaging (diffusion MR), and CSF (p-tau, t-tau, and Aβ1-42). RESULTS Thirty-six (90%; [supranutritional n = 18, control/placebo n = 18]) patients completed the trial. There were no differences in the incidence of specific AEs between groups. Only one secondary biomarker, diffusion MR measures, showed group differences, with less deterioration in the supranutritional group (p < 0.05). CONCLUSION Treatment with VEL015 at doses up to 30 mg per day for 24 weeks was safe and well-tolerated in patients with AD. Diffusion MR measures appear to be the most sensitive biomarkers to assess disease progression over 24 weeks.

Short-term white matter alterations in Alzheimer's disease characterized by diffusion tensor imaging

To investigate whether there are any white matter changes in a 6‐month follow‐up of mild‐moderate Alzheimers patients using diffusion tensor imaging (DTI).

Early childhood trauma and hippocampal volumes in patients with epileptic and psychogenic seizures

OBJECTIVE Exposure to early life childhood trauma has been implicated as resulting in a vulnerability to epileptic and psychogenic nonepileptic seizures (PNES), hippocampal atrophy, and psychiatric disorders. This study aimed to explore the relationships between childhood trauma, epilepsy, PNES, and hippocampal volume in patients admitted to a video-electroencephalogram monitoring (VEM) unit. METHODS One hundred thirty-one patients were recruited from the Royal Melbourne Hospital VEM unit. The diagnostic breakdown of this group was: temporal lobe epilepsy (TLE) (32), other epilepsy syndromes (35), PNES (47), other nonepileptic syndromes (5), both epilepsy and PNES (6), and uncertain diagnosis (6). All patients completed a questionnaire assessing exposure to childhood trauma, the Childhood Trauma Questionnaire (CTQ), as well as questionnaires assessing psychiatric symptomatology (SCL-90-R), Anxiety and Depression (HADS), quality of life (QOLIE-98) and cognition (NUCOG). Volumetric coronal T1 MRI scans were available for 84 patients. Hippocampal volumes were manually traced by a blinded operator. RESULTS The prevalence of childhood trauma in patients with PNES was higher than in patients with other diagnoses (p=0.005), and the group with PNES overall scored significantly higher on the CTQ (p=0.002). No association was found between CTQ scores and hippocampal volumes; however, patients with a history of sexual abuse were found to have smaller left hippocampal volumes than patients who had not (p=0.043). Patients reporting having experienced childhood trauma scored lower on measures of quality of life and higher on measures of psychiatric symptomatology. SIGNIFICANCE Patients with PNES report having experienced significantly more childhood trauma than those with epileptic seizures, and in both groups there was a relationship between a history of having experienced sexual abuse and reduced left hippocampal volume. Patients with PNES and those with epilepsy who have a history of childhood trauma have overall worse quality of life and more psychiatric symptomatology.

Semi‐automated hippocampal segmentation in people with cognitive impairment using an age appropriate template for registration

To evaluate a new semi‐automated segmentation method for calculating hippocampal volumes and to compare results with standard software tools in a cohort of people with subjective memory complaints (SMC) and mild cognitive impairment (MCI).

Assessment of Optic Pathway Structure and Function in Patients With Compression of the Optic Chiasm: A Correlation With Optical Coherence Tomography

PURPOSE The purpose of this study was to investigate correlations between retinal fiber thickness measured by optical coherence tomography (OCT) and anterograde functional and structural differences in the optic pathway of patients with compression of the optic chiasm. Our hypothesis was that loss of visual acuity caused by chronic compressive pathologies may lead to an irreversible decline in vision because of permanent neurodegeneration of the optic radiations and visual cortex. METHODS Quantitative OCT, functional magnetic resonance imaging (MRI) and diffusion tensor MRI measurements were made in 17 patients being surgically treated for chiasmal compression. RESULTS In our study we found that surgically irreversible visual field defects and reduced retinal nerve fiber layer thickness were significantly associated with lower fractional diffusion anisotropy and higher diffusivities in optic radiations and less functional MRI activation in the visual cortex. CONCLUSIONS Damage to the retinal nerve fiber layer is associated with downstream structural and functional degradation of the optic pathway. This may be related to trans-synaptic degeneration and the fact that these factors are important potential imaging biomarkers for predicting visual recovery after surgical decompression.